Composition for inhibiting increase of blood sugar level or lowering blood sugar level

ABSTRACT

A composition for inhibiting an increase in, or lowering, a blood sugar level, which comprises, as a main component, a concentrate of a hot water or alcohol extract of leaves of Lagerstroemia Speciosa, Linn. or Pers. and has an corosolic acid content of 0.01 to 15 mg per 100 mg of the concentrate, and a method of inhibiting an increase in, or lowering, a blood sugar level by oral administration of the composition.

DETAILED DESCRIPTION OF THE INVENTION

1. 1. Field of the Invention

2. The present invention relates to a composition for inhibiting anincrease of a blood sugar level or lowering a blood sugar level. Morespecifically, it relates to a composition for inhibiting an increase ofa blood sugar level or lowering a blood sugar level, which compositioncontains extract components from Lagerstroemia Speciosa, Linn. or Pers.as a main component and has a specific content of corosolic acid.

3. 2. Prior Art of the Invention

4. Lagerstroemia Speciosa, Linn. or Pers. comes under the loosestrifefamily of Myrtales and is generally called “queen's crape myrtle” aswell, and it occurs widely in south east Asian areas including thePhilippines, India, Malaysia, southern China and Australia. In thePhilippines in particular, dry leaves and flowers of LagerstroemiaSpeciosa, Linn. or Pers. are decoted and taken as a drink. This drink isalso well known as a folk medicine against diabetes.

5. Leaves of Lagerstroemia Speciosa, Linn. or Pers. have receivedattention and an extract thereof has been analyzed for obtaining somecomponents. It has been accordingly reported that corosolic acid iscontained as one of the components and that the corosolic acid has beenstudied for its activity by using Ehrlich Ascites Tumour Cells to showthat it is a substance which activates the mobility of grape sugar[Chem. Pharm. Bull. 41(12) 2129-2131 (1993)].

6. The above report is concerned with results of in vitro experimentsand merely suggests results of first-stage discrimination test ofanti-diabetes activities of corosolic acid.

7. JP-A-5-310587 discloses an anti-diabetes preparation containing, asan ingredient, a concentrated dry substance (Lagerstroemia Speciosa,Linn. or Pers. powder extract) obtained by extracting leaves ofLagerstroemia Speciosa, Linn. or Pers. in hot water or an organicsolvent. The above preparation is an easily prepared and high-safetyanti-diabetes preparation by produced by taking out a water-solublefraction and a lipid-soluble fraction from an extract of leaves ofLagerstroemia Speciosa, Linn. or Pers. and adjusting it to a dryextract. The above publication discloses a preferred embodiment in whichthe powder extract is diluted, e.g., in a concentration of 2% and takenas a drink, and the anti-diabetes activity thereof is confirmed by ananimal experiment using mice diseased with diabetes.

8. As already described, dry leaves of Lagerstroemia Speciosa, Linn. orPers. have been used as having an effect on the therapy of diabetes infolk medicine. However, it is not clearly known what component(s) of theleaves of Lagerstroemia Speciosa, Linn. or Pers. has/have humananti-diabetes activity. It is known that corosolic acid is contained asone component, while the activity thereof is a mere result of a study ofthe function to activate the mobility of grape sugar in an in vitroexperiment using cells.

9. Further, there has been no specific clinical knowledge ofcomponent(s) of the extract of leaves of Lagerstroemia Speciosa, Linn.or Pers. which has/have activity in the therapy of human diabetes.Moreover, there has been found no knowledge obtained by studying arelationship between component(s) of the extract of leaves ofLagerstroemia Speciosa, Linn. or Pers. and an increase in a human bloodsugar level.

10. The present inventor has therefore studied a relationship betweencomponent(s) of an extract of leaves of Lagerstroemia Speciosa, Linn. orPers. and an increase or inhibition of an increase in human blood sugarlevel on the basis of clinical tests. When a composition which was aconcentrated extract of leaves of Lagerstroemia Speciosa, Linn. or Pers.and which had a specific content of corosolic acid was administered tomild-case diabetes patients who had a fasting blood sugar level ofslightly higher than approximately 110 mg/dl and who wereinsulin-non-dependent, it was found that an increase in blood sugarlevel was inhibited and that the blood sugar levels decreased onaverage.

11. According to studies by the present inventors, it has been alsofound that the composition which had a specific content of corosolicacid can be obtained by extracting, concentration and drying leaves ofLagerstroemia Speciosa, Linn. or Pers., under a specific condition.

12. Means to Solve the Problems

13. According to the present invention, therefore, there is provided acomposition for inhibiting an increase in, or lowering, a blood sugarlevel, which comprises, as a main component, a concentrate of a hotwater or alcohol extract of leaves of Lagerstroemia Speciosa, Linn. orPers. and has an corosolic acid content of 0.01 to 15 mg per 100 mg ofthe concentrate.

14. According to the present invention, further, there is provided amethod of inhibiting an increase in a blood sugar level, which comprisesorally administering the above composition to a patient who is expectedto suffer an increase in blood sugar level from a normal blood sugarlevel.

15. Further, according to the present invention, there is provided amethod of lowering a blood sugar level to a normal level, whichcomprises orally administering the above composition to a mild-casediabetes patient having a blood sugar level higher than a normal levelto some extent or a serious diabetes patient having a high blood sugarlevel.

16. The present invention will be explained more specificallyhereinafter.

17. Corosolic acid is one of triterpenoids having the followingstructural formula.

18. It is considered that the activity of the composition of the presentinvention in inhibiting an increase in, or lowering, a human blood sugarlevel is caused by the interaction of a specific content of corosolicacid in the concentrate and extracted components of leaves ofLagerstroemia Speciosa, Linn. or Pers.

19. Leaves of Lagerstroemia Speciosa, Linn. or Pers. used as a rawmaterial for the composition of the present invention refer to greenleaves of Lagerstroemia Speciosa, Linn. or Pers. which occurs in thePhilippines or some other areas or a dry product prepared by drying thesame. The green leaves may be dried by leaving it in atmosphere, byair-drying or by forcible drying. Preferably, the drying is carried outby so-called toasted-drying until the leaves have a water content of 20%by weight or less, preferably 10% by weight or less, for preventing thegrowth of microorganisms and attaining storage stability.

20. Green leaves of Lagerstroemia Speciosa, Linn. or Pers. may beextracted as they are, while it is desirable to pulverize the dry leavesor cut them into pieces before the extraction.

21. The method and condition of extracting leaves of LagerstroemiaSpeciosa, Linn. or Pers. in hot water or an alcohol and concentratingthe extract are not specially limited, while there should be employed amethod and a condition under which a resultant concentrate has aspecific content of corosolic acid. That is, the concentrate preferablyhas a corosolic acid content of 0.01 to 15 mg per 100 mg of theconcentrate (dry solid substance). The corosolic acid content per 100 mgof the concentrate is preferably 0.1 to 15 mg, more preferably 0.2 to 12mg, particularly preferably 0.5 to 10 mg.

22. In the composition of the present invention, those components of theleaves of Lagerstroemia Speciosa, Linn. or Pers. which are other thecorosolic acid also have an effect on the activity, and it is requiredto take account of components to be extracted and a concentrating methodand condition with regard to the other components. A preferredembodiment of a proper method and a proper condition will be apparentfrom an explanation to be given later.

23. Method 1

24. In this method, a pulverization product of dry leaves ofLagerstroemia Speciosa, Linn. or Pers. (raw material) added to ethanolor an ethanol aqueous solution (ethanol content 50 to 80% by weight) inan amount 5 to 20 times, preferably 8 to 10 times the weight of the rawmaterial, and the mixture is refluxed under heat at a temperaturebetween room temperature and 90° C., preferably approximately between50° C. and 80° C., for 30 minutes to 2 hours. The above extraction isrepeated twice or three times. The resultant extract may be decolorizedas required by adding 5 to 10 % by weight, based on the raw material, ofactivated carbon. The decolorization is useful for expanding the userange of the composition of the present invention to foods, and thelike. Then, the extract is filtered and concentrated at a temperature of60° C. or lower under reduced pressure to obtain a solid, and the solidis dried at a temperature between 50° C. and 70° C. under reducedpressure (higher reduction rate than that during the concentration). Thethus-obtained solid is pulverized to obtain a powdery concentrate. Theconcentrate obtained by the above method has a specific content ofcorosolic acid and contains an effective amount of other components aswell.

25. Method 2

26. This method is an extraction method using methanol or a methanolaqueous solution. In this method, the extraction is carried out inmethanol or a methanol aqueous solution (methanol content 50 to 90% byweight) in an amount 3 to 20 times the weight of the raw material. Theextraction procedure is preferably carried out at a temperature betweenroom temperature and 65° C. for 30 minutes to 2 hours. The number oftimes of the extraction procedure is not limited to once, and theextraction procedure may be carried out twice or more. The obtainedextract is decolorized as required, and concentrated under the sameconditions as those in the above method 1, whereby a solid can beobtained.

27. Method 3

28. This method 3 is an extraction method using hot water. There is usedhot water in an amount 3 to 20 times the weight of the raw material, andthe extraction is carried out at a temperature between 50° C. and 90°C., preferably between 60° C. and 85° C., for 30 minutes to 2 hours.Desirably, the concentration and drying after the extraction are carriedout for a relatively short period of time since active components may besometimes deteriorated when the concentrate is maintained at a hightemperature for a long period of time. For this reason, it isadvantageous to carry out the concentration and the drying under reducedpressure.

29. The above-explained methods 1 to 3 have been described forexplaining basic methods and conditions, and these methods may bealtered and/or combined as required. For example, the method 1 and themethod 2 may be combined. Of the above methods 1 to 3, the methods 1 and2 are preferred, and the method 1 is particularly preferred.

30. Function and effect of the composition of the present invention

31. When used as a preparation for inhibiting an increase in, orlowering, the blood sugar level, the composition of the presentinvention has the following advantages.

32. (a) It has been reported that conventional oral preparations for thetherapy of diabetes such as a sulfonyl urea preparation, a biguanidepreparation, an insulin resistant amelioration preparation, etc., causesside effects such as hepatopathy, disorder of digestive organs, nausea,vomitting, etc., while the composition of the present invention is freeof these side effects.

33. (b) The above conventional preparations for the therapy of diabetesend their effects when the administration thereof is discontinued, whilethe composition of the present invention continues to have an effect andhas a continuing effect like traditional Chinese medicine since theblood sugar level does not increase when its administration isdiscontinued.

34. (c) The composition of the present invention does not cause adecrease in the blood sugar level when people having a normal bloodsugar level takes it.

35. (d) It is considered that the above advantages of the composition ofthe present invention are exhibited since corosolic acid contained inleaves of Lagerstroemia Speciosa, Linn. or Pers. activates grape sugartransportation even if its concentration is very low.

36. It is considered that intensification of the grape sugartransportation activity of corosolic acid in “intaking of sugar” and“conversion of sugar to energy” is a function different from that ofconventional preparations for the therapy of diabetes.

37. (e) It is also assumed that the composition of the present inventionhas another activity in inhibiting the digestion and absorption ofglucide by preventing the function of typical digestive enzyme ofglucide. It is considered that the above activity is caused by theinteraction of corosolic acid and other component(s) in the concentratedextract of leaves of Lagerstroemia Speciosa, Linn. or Pers.

38. The composition of the present invention can therefore inhibit anincrease in a blood sugar level by orally administering it to patientswho are expected to suffer an increase in blood sugar level from anormal blood sugar level. The above oral administration can be continuedfor a long period of time, and even if the composition of the presentinvention is continuedly taken for a long period of time, the bloodsugar level comes to be lower than a normal blood sugar level in nocase. Further, the oral administration causes no or almost no otherharms or side effects.

39. Further, when orally administered to diabetes patients, thecomposition of the present invention can lower their blood sugar levelto a normal level. The composition of the present invention can work onany one of mild-case patients having a blood sugar level higher than anormal blood sugar level to some extent and serious patients having aconsiderably higher blood sugar level.

40. When the composition of the present invention is orallyadministered, desirably, the dosage of the concentrate having acorosolic acid content of 0.01 to 15 mg per kg of a human body weightper day is 50 mg to 1,000 mg, preferably 70 mg to 800 mg. Specifically,the oral administration is preferably separated to twice or three timesa day. Desirably, further, the oral administration of the composition ofthe present invention is conducted continuedly for at least one month,preferably for at least three months.

41. The composition of the present invention may have the prepartionform of a powder or granules, and it may also have the preparation formof a tablet such as pellets or an encapsulated preparation.

EXAMPLES

42. The present invention will be explained more specifically withreference ot Examples hereinafter.

Example 1

43. (1) Preparation of concentrate from dry leaves of LagerstroemiaSpeciosa, Linn. or Pers.

44. 1 Kg of dry leaves of Lagerstroemia Speciosa, Linn. or Pers. fromthe Philippines were cut, placed in 5 liters of a 80 wt % ethanolaqueous solution and extracted under reflux under heat (approximately85° C.) for 1.5 hours. After the extraction, the leaves of LagerstroemiaSpeciosa, Linn. or Pers. were separated by filtration, again placed a 80wt % ethanol aqueous solution and extracted under reflux under heat(approximately 85° C.) for 1.5 hours. The leaves of LagerstroemiaSpeciosa, Linn. or Pers. were separated by filtration. Extracts obtainedby the first and second extraction procedures were combined, and 500 gof activated carbon was added to carry out decolorization. After theactivated carbon was removed, ethanol and water were removed underreduced pressure at 60° C. to give a concentrate. Then, the concentratewas maintained further under reduced pressure at 60° C. to give a drysolid. The solid was pulverized to give 150 g of a powdery concentrate.

45. (2) Analysis of corosolic acid

46. 1 Grams of the powdery concentrate obtained in the above (1) wasdissolved in 10 ml of methanol and analyzed by high-performance liquidchromatography (HPLC) to show a corosolic acid content of 30 mg in theabove concentrate (corresponding to 3 mg of corosolic acid per 100 mg ofthe concentrate).

47. (3) Preparation of tablet

48. The powdery concentrate obtained in the above (1) was used toprepare tablets containing the following components for a clinical test.TABLE 1 Components % by weight Powdery concentrate 50 Dietary fiber*¹ 20Sucrose fatty acid ester 3 Lactose 22 Hardened oil*² 5 100

49. The above components were homogeneously mixed and prepared intotablets having a weight of 250 mg each (“tablets A” hereinafter) with atablet machine.

50. Further, tablets containing no powdery concentrate (“tablets B”hereinafter) which were indistinguishable from the tablets A wereprepared in the same manner as above except that diluents alone wereused without the powdery concentrate.

51. (4) Clinical test

52. Twenty-two mild-case insulin non-dependent patients having a afasting blood sugar level of approximately 100 to 210 mg/dl wereclassified into two groups.

53. The Group I (11 patients of one group) were allowed to take threetablets A each time after meals three times a day with a cup of waterfor 4 weeks from the beginning of the first to the end of the fourthweek, and the tablets B were administered under the same conditions for4 weeks from the beginning of the fifth week.

54. On the other hand, the Group II (11 patients of the other group)were allowed to take three tablets B each time after meals three times aday with a cup of water for 4 weeks from the beginning of the first tothe end of the fourth week, and the tablets A were administered underthe same conditions for 4 weeks from the beginning of the fifth week.

55. In the beginning of the administration, after 4 weeks and after 8weeks from the administration, bloods of the patients were sampled threetimes and studied for blood sugar levels. Table 1 shows the results.TABLE 1 Group I (11 patients) Average (mg/dl) Group II (11 patients)Average (mg/dl)

56. The tablets A were studied for a significant difference to show aProb>(T) value of 0.0030 and that the tablets A had a high-degreesignificant difference in decreasing the blood sugar level.

What is claimed is:
 1. A composition for inhibiting an increase in, orlowering, a blood sugar level, which comprises, as a main component, aconcentrate of a hot water or alcohol extract of leaves of LagerstroemiaSpeciosa, Linn. or Pers. and has an corosolic acid content of 0.01 to 15mg per 100 mg of the concentrate.
 2. The composition of claim 1 , whichhas the form of an orally administered tablet.
 3. The composition ofclaim 1 , wherein the leaves of Lagerstroemia Speciosa, Linn. or Pers.are dry leaves of Lagerstroemia Speciosa, Linn. or Pers.
 4. Thecomposition of claim 1 , which has an corosolic acid content of 0.1 to15 mg per 100 mg of the concentrate.
 5. A method of inhibiting anincrease in a blood sugar level, which comprises orally administeringthe composition of claim 1 to a patient who is expected to suffer anincrease in blood sugar level from a normal blood sugar level.
 6. Themethod of claim 5 , wherein the composition of claim 1 is orallyadministered to the patient at a dose, as a concentrate, of 50 mg to1,000 mg per kg of a human body weight per day.
 7. A method of loweringa blood sugar level to a normal level, which comprises orallyadministering the composition of claim 1 to a diabetes patient having ablood sugar level higher than a normal level.
 8. The method of claim 7 ,wherein the composition of claim 1 is orally administered to the patientat a dose, as a concentrate, of 50 mg to 1,000 mg per kg of a human bodyweight per day.